Process for producing 2-phenylacetophenone derivatives and precursons therefor

ABSTRACT

A process for producing 2-phenylacetophenone derivatives represented by the formula (I):  
                 
 
     (wherein X is an alkyl group or a haloalkyl group, and Y is a hydrogen atom, a halogen atom or an alkyl group which may be substituted), which comprises reacting a compound represented by the formula (II):  
                 
 
     (wherein X and Y are as defined above, and R is a hydrogen atom or an alkyl group) with an acid.

TECHNICAL FIELD

[0001] The present invention relates to a process for producing2-phenylacetophenone derivatives represented by the after-mentionedformula (I) which are useful as intermediates for various chemicalproducts, pharmaceuticals and agricultural chemicals, and precursors forthe production thereof.

BACKGROUND ART

[0002] 2-phenylacetophenone derivatives represented by theafter-mentioned formula (I) are disclosed, for example, inJP-A-5-279312, JP-A-4-270248 and Japanese Patent No. 2,805,255, and theycan be produced by conventional methods and also by the methodsdisclosed in these publications. However, by these production methods,it has been difficult to produce the derivatives depending upon thetypes of the substituents X, Y and R or the positions to be substituted,or they can be produced only by a complicated production processinvolving many reaction steps. Further, a process proposed to solve suchproblems as disclosed in JP-A-2000-132290, employs an expensivetransition metal catalyst, and in an industrial operation, the catalystis required to be recovered and reused.

[0003] Compounds similar to the compounds represented by theafter-mentioned (II) as the precursors for the production of2-phenylacetophenone derivatives of the present invention are disclosed,for example, in J. Org. Chem. 2000, 65, 6398-6411, JP-A-60-13730,JP-A-60-13759, JP-A-2-13963 and JP-A-11-510163, but the compoundsrepresented by the formula (II) are not disclosed.

DISCLOSURE OF THE INVENTION

[0004] It is an object of the present invention to produce2-phenylacetophenone derivatives which used to be difficult toindustrially produce by conventional methods, efficiently and in a shortreaction process by using starting materials which are industriallyreadily and inexpensively available.

[0005] The present invention provides a process for producing2-phenylacetophenone derivatives represented by the formula (I):

[0006] (wherein X is an alkyl group or a haloalkyl group, and Y is ahydrogen atom, a halogen atom or an alkyl group which may besubstituted), characterized by reacting a compound represented by theformula (II):

[0007] (wherein X and Y are as defined above, and R is a hydrogen atomor an alkyl group) with an acid.

[0008] Further, the present invention provides such a process forproducing 2-phenylacetophenone derivatives, which comprises:

[0009] (1) a first stage of reacting a compound represented by theformula (III):

[0010] (wherein X is an alkyl group or a haloalkyl group, and Hal is ahalogen atom) with a compound represented by the formula (IV):

[0011] (wherein Y is a hydrogen atom, a halogen atom or an alkyl groupwhich may be substituted; and R is a hydrogen atom or an alkyl group) inthe presence of a base and a solvent, to produce a compound representedby the formula (II):

[0012] (wherein X, Y and R are as defined above); and

[0013] (2) a second stage of reacting the compound of the formula (II)produced in the first stage with an acid to produce a2-phenylacetophenone derivative represented by the formula (I):

[0014] (wherein X and Y are as defined above).

[0015] Further, the present invention provides a compound represented bythe formula (II):

[0016] (wherein X is an alkyl group or a haloalkyl group, Y is ahydrogen atom, a halogen atom or an alkyl group which may besubstituted, and R is a hydrogen atom or an alkyl group), as a precursorfor the production of the above-mentioned 2-phenylacetophenonederivatives.

BEST MODE FOR CARRYING OUT THE INVENTION

[0017] In the present invention, the alkyl group or the alkyl moietyrepresented by X and Y contained in the formulae (I) and (II) maypreferably be one having from 1 to 6 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl or hexyl. Thehalogen atom may be an atom of fluorine, chlorine, bromine or iodine.

[0018] The substituent for the alkyl group which may be substituted,represented by Y in the formulae (I) and (II), may preferably be ahalogen atom; an alkoxy group which may be substituted by halogenatom(s); or an alkylthio group which may be substituted by halogenatom(s). The number of such substituents may be 1 or more, and in thecase of more than 1, such substituents may be the same or different.Further, the alkyl moiety of the above alkoxy or alkylthio group maypreferably be one having from 1 to 6 carbon atoms, and the halogen atommay be an atom of fluorine, chlorine, bromine or iodine.

[0019] X contained in the formulae (I) and (II) is preferably ahaloalkyl group, or preferably an alkyl group substituted by fluorineatoms, particularly preferably difluoromethyl, trifluoromethyl,2,2,2-trifluoromethyl or heptafluoropropyl, most preferablytrifluoromethyl. Further, Y contained in the formulae (I) and (II) ispreferably a halogen atom, most preferably a fluorine atom.

[0020] The alkyl group represented by R contained in the formula (II) ispreferably one having from 1 to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, pentyl or hexyl.

[0021] The compound of the formula (II) may be in the form of a saltwith an acidic substance or a basic substance. The salt with an acidicsubstance may, for example, be an inorganic salt such as a hydrochlorideor a sulfate, and, the salt with a basic substance may be a salt with aninorganic base or an organic base, such as a sodium salt, a potassiumsalt, a calcium salt, an ammonium salt or a dimethyl ammonium salt.

[0022] The process of the present invention comprises a first stage ofreacting the compound of the formula (III) with the compound of theformula (IV) in the presence of a base and a solvent to produce thecompound of the formula (II), and a second stage reaction of reactingthe compound of the formula (II) with an acid to produce the compound ofthe formula (I). The reactions of the respective stages will bedescribed in detail hereinafter. Here, the compound of the formula (II)as the reaction product in the first stage is a novel compound. Further,this compound has geometrical isomers i.e. E-isomer and Z-isomer, andsuch respective isomers and a mixture of the isomers are within thescope of the present invention.

[0023] In the reaction of the first stage, the amounts of compounds ofthe formulae (III) and (IV) to be used, vary depending upon the types ofthe respective compounds, the differences in the reaction conditionswhich will be described hereinafter, etc., and can not generally bedefined. However, usually, the compound of the formula (IV) is used in aproportion of from 0.9 to 5.0 mols, preferably from 0.9 to 1.5 mols,more preferably from 0.9 to 1.0 mol, per mol of the compound of theformula (III). When the amounts of both compounds are equimolar amountsor in the vicinity thereof, the compound of the formula (II) can beobtained in good yield, such being industrially advantageous from theviewpoint of e.g. the production costs.

[0024] The reaction temperature and the reaction time in the reaction ofthe first stage, vary depending upon the types of the compounds of theformulae (III) and (IV) and the differences in the reaction conditionswhich will be described hereinafter, and can not generally be defined.However, usually, the reaction temperature is from 0 to 100° C.,preferably from 0 to 40° C. Even when the reaction temperature is roomtemperature or in its vicinity, the compound of the formula (II) can beobtained in good yield, such being industrially advantageous from theviewpoint of e.g. the production costs. Further, the reaction time isusually from 0.1 to 24 hours, preferably from 1 to 6 hours.

[0025] The base which can be used for the reaction of the first stagemay, for example, be a hydride of an alkali metal such as sodium hydrideor potassium hydride; or an organic metal compound such asn-butyllithium. It is particularly preferred to use a hydride of analkali metal, and it is especially preferred to use sodium hydride. Thebase is used usually in a proportion of from 1.0 to 2.0 mols, preferablyfrom 1.0 to 1.5 mols, more preferably from 1.0 to 1.3 mols, per mol ofthe compound of the formula (III). Even if the amount of the base to beused is an equimolar amount with the compound of the formula (III) or inits vicinity, the compound of the formula (II) can be obtained in goodyield, such being industrially advantageous from the viewpoint of e.g.the production costs.

[0026] The solvent which can specifically be used in the reaction of thefirst stage may, for example, be an ether such as tetrahydrofuran ordioxane; an aprotic polar solvent such as dimethylformamide,dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide orsulfolane; an aromatic hydrocarbon such as toluene or chlorobenzene; oran aliphatic hydrocarbon. It is especially preferred to use an aproticpolar solvent, and it is most preferred to use dimethylformamide.

[0027] The reaction of the first stage is preferably carried out in aninert gas atmosphere. As a specific inert gas to be used, any gas inertto the reaction such as nitrogen, argon or helium may be used.

[0028] At the time of setting each of the above-mentioned variousconditions for the reaction of the first stage, i.e. the amounts of thecompounds of the formulae (III) and (IV), various reaction conditionswhich vary depending upon the types of the compounds of the formulae(III) and (IV), the reaction temperature and the reaction time,numerical values are optionally selected within the usual ranges and thepreferred ranges shown for the respective conditions and may be suitablycombined.

[0029] The compound of the formula (IV) as the starting material of thereaction of the first stage is a compound disclosed in e.g.JP-A-52-90630, U.S. Pat. No. 4,551,526 or U.S. Pat. No. 5,017,723.However, a compound represented by the formula (IV′):

[0030] (wherein R is a hydrogen atom or an alkyl group) is notspecifically disclosed in these prior art references.

[0031] The compound of the formula (IV) can be produced by a method inaccordance with the disclosure in column 15, lines 20 to 62 of U.S. Pat.No. 5,017,723. Specifically, it can be produced by reacting a compoundrepresented by the formula (V):

[0032] (wherein Y is a hydrogen atom, a halogen atom or an alkyl groupwhich may be substituted) with a compound represented by the formula(VI): M-CN (wherein X is an alkali metal element) and a compoundrepresented by the formula (VII): R₂NH (wherein R is a hydrogen atom oran alkyl group) or its salt.

[0033] The compound represented by the formula (VI) is preferably sodiumcyanide or potassium cyanide.

[0034] The reaction of the compound of the formula (V) with the compoundof the formula (VI) and the compound of the formula (VII) is carried outin the presence of an acid. As such an acid, a mineral acid such ashydrochloric acid or sulfuric acid may be mentioned. In such a case, theacid is used usually in a proportion of from 0.2 to 1.0 mol per mol ofthe compound of the formula (VII).

[0035] Further, in a case where the compound of the formula (V) isreacted with the compound of the formula (VI) and a salt of the compoundof the formula (VII), the salt of the compound of the formula (VII),may, for example, be a salt with a mineral acid such as hydrochloricacid or sulfuric acid.

[0036] In the above-mentioned method for producing the compound of theformula (IV), the amounts of the compounds of the formulae (V), (VI) and(VII) vary depending upon the types of the respective compounds, thedifferences in the reaction conditions which will be describedhereinafter, etc. and can not generally be defined. However, thecompound of the formula (VI) is used usually in a proportion of from 0.8to 3.0 mols per mol of the compound of the formula (V). Further, thecompound of the formula (VII) is used usually in a proportion of from0.8 to 3.0 mols per mol of the compound of the formula (V).

[0037] The reaction temperature and the reaction time in the reactionfor producing the compound of the formula (IV) vary depending upon thetypes of the compounds of the formulae (V), (VI) and (VII), thedifferences in the reaction conditions which will be describedhereinafter, etc. and can not generally be defined. However, thereaction temperature is usually within a range of from 5° C. to thereflux temperature. Further, the reaction time is usually from 1 to 24hours.

[0038] The above-described reaction for producing the compound of theformula (IV) is preferably carried out in the presence of a solvent. Thesolvent which can specifically be used, may, for example, be water; analcohol such as methanol; a mixed solvent of water with an alcohol;acetonitrile; or an aromatic hydrocarbon such as toluene orchlorobenzene.

[0039] At the time of setting each of the above-mentioned variousconditions in the reaction for producing the compound of the formula(IV) i.e. the amounts of the compounds of the formulae (V), (VI) and(VII), various reaction conditions which vary depending upon the typesof the compounds of the formulae (V), (VI) and (VII), the reactiontemperature and the reaction time, numerical values are optionallyselected within the usual ranges and the preferred ranges shown for therespective conditions and may be suitably combined.

[0040] After completion of the reaction in the first stage, the compoundof the formula (II) may be isolated from the reaction system by a usualmethod and may be purified by a distillation method, a recrystallizationmethod or the like, as the case requires. The compound of the formula(II) thus isolated and purified, can be supplied as the startingmaterial for the reaction of the second stage. However, the compound ofthe formula (II) can be subjected to the reaction of the second stagewithout isolating or purifying it from the reaction system for thereaction in the first stage, and accordingly, the reaction of the firststage and the reaction of the second stage can be carried outcontinuously in the same reactor, whereby the production cost can bereduced, such being industrially advantageous.

[0041] As the acid to be used for the reaction of the second stage, amineral acid such as hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid or phosphoric acid; or an organic acid such as aceticacid or propionic acid, may, for example, be mentioned. It isparticularly preferred to use a mineral acid, and among mineral acids,it is especially preferred to use hydrochloric acid or sulfuric acid.The amount of the acid to be used varies depending upon the type of thecompound of the formula (II) and the differences in the reactionconditions which will be described hereinafter and can not generally bedefined. However, it is used usually in a proportion of from 1 to 30mols, preferably from 1.5 to 15 mols, more preferably from 1.5 to 8mols, per mol of the compound of the formula (II).

[0042] The reaction temperature and the reaction time for the reactionof the second stage vary depending upon the type of the compound of theformula (II) and the differences in the reaction conditions which willbe described hereinafter and can not generally be defined. However, thereaction temperature is usually from 25 to 140° C., preferably from 70to 120° C. Further, the reaction time is usually from 0.1 to 24 hours,preferably from 0.3 to 4 hours.

[0043] The reaction of the second stage is preferably carried out in thepresence of a solvent. The solvent which can specifically be used, may,for example, be water; an alcohol such as methanol; or a solvent whichis used in the first stage. Further, in a case where an acid whichfunctions also as a solvent, such as acetic acid, is used, it can beused as both an acid and a solvent.

[0044] At the time of setting each of the above-mentioned variousconditions in the second stage, i.e. the amounts of the compound of theformula (II) and the acid, various reaction conditions which varydepending upon the type of the compound of the formula (II) and theacid, the reaction temperature and the reaction time, numerical valuesare optionally selected from the usual ranges and the preferred rangesshown for the respective conditions and may be suitably combined.Further, various conditions in the first stage and various conditions inthe second stage may suitably be combined.

[0045] After completion of the reaction of the second stage, the2-phenylacetophenone derivative of the formula (I) can be isolated fromthe reaction system by a usual method and, if necessary, can be purifiedby a distillation method, a recrystallization method or the like.

[0046] Now, some of preferred embodiments in the present invention willbe exemplified.

[0047] (1) A process which comprises reacting a compound of the formula(II) with an acid to produce a 2-phenylacetophenone derivative of theformula (I).

[0048] (2) The process of (1) which comprises a first stage of reactinga compound of the formula (III) with a compound of the formula (IV) inthe presence of a base and a solvent to produce a compound of theformula (II); and a second stage of reacting the compound of the formula(II) produced in the first stage, with an acid to produce a2-phenylacetophenone derivative of the formula (I).

[0049] (3) The process of (2) which comprises a first stage of reactinga compound of the formula (V) with a compound of the formula (VI) and acompound of the formula (VII) or its salt, to produce a compound of theformula (IV), which is reacted with a compound of the formula (III) inthe presence of a base and a solvent, to produce a compound of theformula (II); and a second stage of reacting the compound of the formula(II) produced in the first stage, with an acid to produce a2-phenylacetophenone derivative of the formula (I).

[0050] (4) The process of (1), (2) or (3) wherein the compound of theformula (II) is reacted with a mineral acid.

[0051] (5) The process of (2) or (3) wherein the reaction of the firststage and the reaction of the second stage is continuously carried outin the same reactor.

[0052] (6) A process for producing a compound of the formula (IV), whichcomprises reacting a compound of the formula (V) with a compound of theformula (VI) and a compound of the formula (VII).

[0053] (7) A process for producing a compound of the formula (II), whichcomprises reacting a compound of the formula (III) with a compound ofthe formula (IV) in the presence of a base and a solvent.

[0054] (8) The process of (2), (3), (5) or (7), wherein the reaction toproduce the compound of the formula (II) from the compound of theformula (III), is carried out in the presence of an inert gas.

[0055] (9) The process of (2), (3), (5), (7) or (8), wherein thereaction to produce the compound of the formula (II) from the compoundof the formula (III), is carried out at a reaction temperature of from 0to 100° C.

[0056] (10) The process of (9), wherein the reaction to produce thecompound of the formula (II) from the compound of the formula (III), iscarried out at a reaction temperature of from 0 to 40° C.

EXAMPLE 1

[0057] Preparation of2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile

[0058] Into a 1 l four-necked flask equipped with a thermometer, astirrer and a dropping funnel, 49.6 g (0.4 mol) of 4-fluorobenzaldehydeand 480 ml of acetonitrile were charged, and a solution comprising 29.4g (0.64 mol) of sodium cyanide, 81.6 g (1 mol) of dimethylaminehydrochloride and 200 ml of water, was dropwise added over a period of15 minutes at from 20 to 30° C. with stirring, and then reacted at thesame temperature for 18 hours. After completion of the reaction, themixture was subjected to liquid separation. The organic layer wasseparated, and acetonitrile was distilled off. The residue was extractedwith 400 ml of ethyl acetate, washed with a 5% sodium hydrogen carbonateaqueous solution and water, and then dried over anhydrous sodiumsulfate. Ethyl acetate was distilled off, and the obtained oilysubstance was distilled under reduced pressure to obtain 64.5 g (yield:90.5%) of the desired compound (boiling point: 100-101° C./1 KPa). TheNMR spectrum data thereof are as follows.

[0059]¹H-NMR δ ppm (Solvent: CDCl₃/400 MHz) 2.29(s,6H), 4.79(s,1H),7.07(m,2H), 7.48(m,2H)

EXAMPLE 2

[0060] Preparation of2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile

[0061] Into a 1 l four-necked flask equipped with a thermometer, astirrer and a dropping funnel, 30.9 g (0.6 mol) of sodium cyanide, 85.7g (1.05 mol) of dimethylamine hydrochloride, 1.2 g ofbenzyltri-n-butylammonium chloride and 200 ml of water were charged, anda solution comprising 62.1 g (0.5 mol) of 4-fluorobenzaldehyde and 150ml of toluene, was dropwise added over a period of 30 minutes at from 20to 30° C. with stirring, and then reacted at from 45 to 50° C. for 4hours. After completion of the reaction, 200 ml of water was added, andthe mixture was subjected to liquid separation. The organic layer wasseparated, washed with a 5% sodium hydrogen carbonate aqueous solutionand water, and then dried over anhydrous sodium sulfate. Toluene wasdistilled off, and the obtained oily substance was distilled underreduced pressure to obtain 79.3 g (yield: 89%) of the desired compound(boiling point: 100-101° C./1 KPa).

EXAMPLE 3

[0062] Preparation of1-(4-fluorophenyl)-2-(4-trifluoromethylphenyl)-N,N-dimethylethenylamine

[0063] Into a 200 ml four-necked flask equipped with a thermometer, astirrer, a dropping funnel and a N₂ gas supply tube, a N₂ gas wasintroduced so that the interior of the flask became a N₂ atmosphere. 40ml of dimethylformamide and 2.4 g (61.6 mmol) of sodium hydride (62% oilsuspension) were charged, and a solution comprising 10 g (56 mmol) of2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile and 10.9 g (56mmol) of 4-(trifluoromethyl)benzyl chloride, was dropwise added over aperiod of one hour at from 5 to 10° C. under cooling with ice water andthen further reacted at from 20 to 30° C. for one hour. After completionof the reaction, 200 ml of water was added, and the mixture wasextracted with 200 ml of ethyl acetate. The extract was washed with a 5%sodium hydrogen carbonate aqueous solution and water and then dried overanhydrous sodium sulfate. Ethyl acetate was distilled off, and theobtained oily substance was distilled under reduced pressure to obtain15.3 g (yield: 88.3%) of the desired compound (boiling point: 130-135°C./0.6 KPa). The NMR spectrum data thereof were as follows.

[0064]¹H-NMR δ ppm (Solvent: CDCl₃/400 MHz) 2.68(s,6H), 5.42(s,1H),6.71(m,2H), 7.03(m,2H), 7.20 (m,4H)

EXAMPLE 4

[0065] Preparation of 4′-fluoro-2-(4-trifluoromethylphenyl)acetophenone

[0066] Into a 200 ml four-necked flask equipped with a thermometer, astirrer and a reflux condenser, 15.5 g (50 mmol) of1-(4-fluorophenyl)-2-(4-trifluoromethylphenyl)-N,N-dimethylethenylamine,80 ml of acetic acid and 30 ml of concentrated hydrochloric acid werecharged and reacted with stirring for two hours under refluxing underheating by an oil bath. After completion of reaction, 500 ml of waterwas added, and precipitated crystals were collected by filtration andwashed with a 2% sodium hydrogen carbonate aqueous solution and water.Then, the crystals were further washed and purified with 20 ml ofn-hexane and then vacuum-dried to obtain 12.7 g (yield: 90.3%) of thedesired compound (melting point: 93-95° C.) as slightly yellow crystals.

EXAMPLE 5

[0067] Preparation of 4′-fluoro-2-(4-trifluoromethylphenyl)acetophenone

[0068] Into a 1 l four-necked flask equipped with a thermometer, astirrer, a dropping funnel and a N₂ gas supply tube, a N₂ gas wasintroduced so that the interior of the flask became a N₂ atmosphere. 250ml of dimethylformamide and 16.5 g (0.426 mol) of sodium hydride (62%oil suspension) were charged, and a solution comprising 69 g (0.387 mol)of 2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile and 75.4 g(0.387 mol) of 4-(trifluoromethyl)benzyl chloride, was dropwise addedover a period of one hour at from 10 to 15° C. under cooling with icewater and then further reacted at from 20 to 30° C. for one hour. Then,280 ml of 40% sulfuric acid was added to this reaction mixture andreacted at from 80 to 90° C. for one hour. After completion of thereaction, 2 l of water was added, and precipitated crystals werecollected by filtration and washed with a 2% sodium hydrogen carbonateaqueous solution and water. Then, the crystals were further washed andpurified with 100 ml of n-hexane and then vacuum-dried to obtain 97.7 g(yield: 89.4%) of the desired compound (melting point: 93-95° C.) asslightly yellow crystals.

EXAMPLE 6

[0069] Preparation of2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile

[0070] Into a 1 l four-necked flask equipped with a thermometer, astirrer and a dropping funnel, 144.5 g (1.6 mol) of a 50.7%dimethylamine aqueous solution and 118.5 g of water were charged, and159.4 g (0.38 mol) of a 25% of sulfuric acid aqueous solution wasdropwise added over a period of 15 minutes at a temperature of nothigher than 20° C. with stirring. Then, 67.4 g (1.38 mol) of sodiumcyanide was introduced. Then, 155.1 g (1.25 mol) of 4-fluorobenzaldehydewas dropwise added over a period of 20 minutes at from 20 to 30° C.Thereafter, the reaction was carried out at 50° C. for 4 hours. Aftercompletion of the reaction, the reaction mixture was subjected to liquidseparation. The organic layer was separated and washed with 500 ml ofwater of 50° C. to obtain 222.8 g (yield: 98.4%) of the desired compoundhaving a purity of 98.4% (by GC analysis).

EXAMPLE 7

[0071] Preparation of 4′-fluoro-2-(4-trifluoromethylphenyl)acetophenone

[0072] Into a 2 l four-necked flask equipped with a thermometer, astirrer, a dropping funnel and a N₂ gas supply tube, a N₂ gas wassupplied so that the interior of the flask became a N₂ atmosphere. 400ml of dimethylformamide and 35.0 g (0.9 mol) of sodium hydride (62% oilsuspension) were charged, and a mixed solution comprising 133.5 g (0.75mol) of 2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile, 145.9 g(0.75 mol) of 4-(trifluoromethyl)benzyl chloride and 280 ml ofdimethylformamide, was dropwise added over a period of one hour at from10 to 25° C. under cooling with water and then further reacted at from20 to 30° C. for one hour. Then, 330 g of 40% sulfuric acid aqueoussolution was added to this reaction mixture and reacted at from 80 to90° C. for one hour. After completion of the reaction, the reactionproduct was added to 2 e of water, and precipitated crystals werecollected by filtration under reduced pressure and washed with water.Then, the crystals were washed and purified at 20° C. by means of 500 mlof isopropyl alcohol and then dried with hot air to obtain 204.7 g(yield: 95.2%) of the desired compound having a purity of 98.4% (by HPLCanalysis).

INDUSTRIAL APPLICABILITY

[0073] According to the present invention, 2-phenylacetophenonederivatives which used to be difficult to produce on an industrial scaleby conventional method, can be efficiently produced by a short reactionprocess by using a starting material which is industrially readily andinexpensively available.

1. A process for producing 2-phenylacetophenone derivatives representedby the formula (I):

(wherein X is an alkyl group or a haloalkyl group, and Y is a hydrogenatom, a halogen atom or an alkyl group which may be substituted),characterized by reacting a compound represented by the formula (II):

(wherein X and Y are as defined above, and R is a hydrogen atom or analkyl group) with an acid.
 2. The process for producing2-phenylacetophenone derivatives according to claim 1, characterized bycomprising: (1) a first stage of reacting a compound represented by theformula (III):

(wherein x is an alkyl group or a haloalkyl group, and Hal is a halogenatom) with a compound represented by the formula (IV):

(wherein Y is a hydrogen atom, a halogen atom or an alkyl group whichmay be substituted; and R is a hydrogen atom or an alkyl group) in thepresence of a base and a solvent, to produce a compound represented bythe formula (II):

(wherein X, Y and R are as defined above); and (2) a second stage ofreacting the compound of the formula (II) produced in the first stagewith an acid to produce a 2-phenylacetophenone derivative represented bythe formula (I):

(wherein X and Y are as defined above).
 3. The process for producing2-phenylacetophenone derivatives according to claim 2, characterized byreacting a compound represented by the formula (V):

(wherein Y is a hydrogen atom, a halogen atom or an alkyl group whichmay be substituted) with a compound represented by the formula (VI):M-CN (wherein M is an alkali metal element) and a compound representedby the formula (VII): R₂NH (wherein R is a hydrogen atom or an alkylgroup) or its salt, to produce a compound represented by the formula(IV):

(wherein Y and R are as defined above), which is subjected to thereaction of the first stage.
 4. The process according to claim 1 or 2,characterized by using the acid in a proportion of from 1 to 30 mols permol of the compound of the formula (II).
 5. The process according toclaim 1 or 2, characterized by reacting the compound of the formula (II)with a mineral acid.
 6. The process according to claim 2, characterizedby using the compound of the formula (IV) in a proportion of from 0.9 to5.0 mols per mol of the compound of the formula (III).
 7. The processaccording to claim 2, characterized by using the base in a proportion offrom 1.0 to 2.0 mols per mol of the compound of the formula (III). 8.The process according to claim 2, characterized by carrying out thereaction of the first stage in the presence of an inert gas.
 9. Theprocess according to claim 2, characterized by -carrying out thereaction of the first stage at a reaction temperature of from 0 to 100°C.
 10. The process according to claim 2, characterized by carrying outthe reaction of the first stage and the reaction of the second stagecontinuously in the same reactor.
 11. A compound represented by theformula (II):

(wherein X is an alkyl group or a haloalkyl group, Y is a hydrogen atom,a halogen atom or an alkyl group which may be substituted, and R is ahydrogen atom or an alkyl group).